Tumor necrosis factor alpha (TNF-alpha) is implicated in the development of persistent pain. Its expression increases both spinally and supraspinally after peripheral inflammation. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Prefrontal synaptic transmission is potentiated in mice with chronic pain through an enhancement of presynaptic transmitter release. However, it is not known if TNF-alpha expression is altered in the ACC in response to persistent pain and if synaptic transmission within this region is modulated by TNF-alpha. In the present study, we examined TNF-alpha expression in the mouse ACC following hind-paw administration of complete Freund's adjuvant (CFA) and examined the role of TNF-alpha in ACC synaptic transmission. Quantification of TNF-alpha at the protein level (by ELISA) revealed enhanced expression following CFA-induced peripheral inflammation. In vitro whole-cell patch-clamp recordings revealed that TNF-alpha significantly enhanced synaptic transmission through increased probability of neurotransmitter release in the ACC. Our findings provide evidence that presynaptic alterations caused by peripheral inflammation is partly attributable to the up-regulation of TNF-alpha in the ACC.